mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Gene therapy for retinitis pigmentosa
Retinitis pigmentosa is an inherited degenerative eye disease leading to severe impairment and loss of vision 3. Retinitis pigmentosa begins with the abnormalities of the rod photoreceptors (responsible for night vision), which leads to periphery vision loss and nyctalopia (night blindness) 3. The continuous loss of rod photoreceptors will lead to paling of the optical nerve, spreading of pigmentary deposits, and attenuation of retinal vessels 1. After the loss of rods, the cones begin to die, causing nearly total blindness 1. There is no cure for retinitis pigmentosa currently; vitamin A can reduce the progress of the disease in some patients 3. More than thirty genes and over 100 mutations are associated with retinitis pigmentosa 1. Among these mutations, autosomal dominant retinitis pigmentosa (ADRP) is the most common mode of inheritance 1. Research on gene therapy of ADRP is in progress and showed great success on mammalian animal models. In the following are several examples of gene therapy to treat ADRP. Neurotrophin therapy: Neurotrophins are a group of compounds that induce the development, maintenance and function of central nervous system 4. Two neurotrophins: ciliary-derived neurotrophic factor (CNTF) and Glial-derived neurotrophic factor (GDNF) have been delivered by gene transfer as therapeutic approach. CNTF is a member of interleukin-6 family cytokine 1. Virally delivered CNTF has been shown to induce the regeneration of cone outer segments and to preserve the retinal histology months after the photoreceptors begin to degenerate 1. GDNF is a member of the transforming growth factor-beta family 1. Viral delivered GDNF is able to prolong dopaminergic neuron and dorsal root ganglion cell survival in a RHO mutant rat model 1. Both CNTF and GDNF are able to promote cell survival, thus prolong useful vision and therapeutic treatment window. The limitation of neurotrophins treatment is the non-specific actions that might affect other types of cells besides the target cell 1. The short half-life of CNTF (120-400 min) and potential cytotoxicity of GDNF are also disadvantages of neurotrophin treatment therapy 1. Gene replacement and surpression: Whereas neurothropin therapy aims at preservating the function and survival of neurons, gene replacement approach targets the mutant genes associated with retinitis pigmentosa 1. Gene replacement means the delivery of a wild-type rhodopsin gene (rho) into the target cell. However, since photoreceptors are sensitive to the level of rhodopsin, it is necessary to suppress the expression of endogenous rho gene by RNA interference 1. Small RNA molecules (microRNA, small interfering RNA and short hairpin RNA) can form RNA dimers with the mRNA transcribed from the endogenous mutant gene while sparing the introduced wild type RNA 1. This will lead to the degradation of the mutant gene and will aid in the replacement of the wild-type gene 1. The limitations of RNA interference are that shRNA is toxic when overexpressed in the central nervous system and that the off-target effect may cause potential problems in RNA interference application 1. Vectors for gene therapy: Viral mediated delivery is the major approach in ADRP. The common vectors are adenovirus, adeno-associated virus (AAV) and lentivirus 2. Among these viruses, AAV is the most versatile vector for ADRP therapy due to its broad range of host cells. Moreover, AAV has proved its advantages as a vector in treatment of retinal degeneration such as achromatopsia, retinoschisis and retinitis pigmentosa 2. The size of insertion gene is a limitation for AAV because AAV can only accommodate as large as a 4.7 kb gene insert, whereas lentivirus can carry an up to 8 kb insertion 2. Another disadvantage for viral vector is the production of neutralizing antibody, which may inactivate the viral vector and thus undermine the therapeutic effect 2. References: 1. Rossmiller, B., Mao, H. & Lewin, A. S. Review : Gene therapy in animal models of autosomal dominant retinitis pigmentosa . 2479–2496 (2012). 2. Conlon, T. J. et al. Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa . Hum. Gene Ther. Clin. Dev. 24, 23–8 (2013). 3. http://en.wikipedia.org/wiki/Retinitis_pigmentosa 4. http://en.wikipedia.org/wiki/Neurotrophin